title: Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease.
abstract: Parkinson disease is caused by the death of midbrain dopamine neurons from oxidative stress, abnormal protein aggregation, and genetic predisposition. In 2003, Bonifati et al. (23) found that a single amino acid mutation in the DJ-1 protein was associated with early-onset, autosomal recessive Parkinson disease (PARK7). The mutation L166P prevents dimerization that is essential for the antioxidant and gene regulatory activity of the DJ-1 protein. Because low levels of DJ-1 cause Parkinson, we reasoned that overexpression might stop the disease. We found that overexpression of DJ-1 improved tolerance to oxidative stress by selectively up-regulating the rate-limiting step in glutathione synthesis. When we imposed a different metabolic insult, A53T mutant α-synuclein, we found that DJ-1 turned on production of the chaperone protein Hsp-70 without affecting glutathione synthesis. After screening a number of small molecules, we have found that the histone deacetylase inhibitor phenylbutyrate increases DJ-1 expression by 300% in the N27 dopamine cell line and rescues cells from oxidative stress and mutant α-synuclein toxicity. In mice, phenylbutyrate treatment leads to a 260% increase in brain DJ-1 levels and protects dopamine neurons against 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) toxicity. In a transgenic mouse model of diffuse Lewy body disease, long-term administration of phenylbutyrate reduces α-synuclein aggregation in brain and prevents age-related deterioration in motor and cognitive function. We conclude that drugs that up-regulate DJ-1 gene expression may slow the progression of Parkinson disease by moderating oxidative stress and protein aggregation.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, Colorado 80045, USA. wenbo.zhou@ucdenver.edu
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhou
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bercury
authors.forename: Jessica
authors.initials: J
authors.lastname: Cummiskey
authors.forename: Nancy
authors.initials: N
authors.lastname: Luong
authors.forename: Jacob
authors.initials: J
authors.lastname: Lebin
authors.forename: Curt R
authors.initials: CR
authors.lastname: Freed
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors; D051379:Mice; D009474:Neurons; D018696:Neuroprotective Agents; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy*; D054464:Peroxiredoxins; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D000071617:Protein Deglycase DJ-1; D011506:Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D015513:Oncogene Proteins; D010654:Phenylbutyrates; D011506:Proteins; C075773:4-phenylbutyric acid; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1